Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels
Yifeng LinShunni DongXiaohang YeJuan LiuJiaqun LiYanye ZhangMixue TuSiwen WangY. YingRuixue ChenFeixia WangFei-Da NiJianpeng ChenBinyang DuDan Zhang
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Abstract Background: Endometrial injury is one of the major causes of thin endometrium and subfertility. Stem cell-based therapies have made strides towards further efficacious treatment of injured endometrium. However, reported therapeutic stem cells that can be used for thin endometrium are difficult to acquire for large-scale clinical application. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs for their robuster expansion ability, lower immunogenicity as well as extensive sources. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms. Methods: The murine endometrial injury model was established by ethanol (95%) perfusion, with further intrauterine instillation of treating materials. The retention time of HP-MSCs was detected by in vivo imaging and ex vivo frozen section. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry (Ki67). The stromal and glandular cells were isolated from the human endometrium to determine proliferation, migration, signaling pathway changes via EdU assay, transwell migration assay, and western blot respectively. Results: Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri compared with normal HP-MSCs. In vitro data showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness, decrease fibrous area, promote the proliferation of endometrial cells, and improve the embryo implantation rate. In vitro assays indicated that HP-MSCs-HA could not only promote the proliferation and migration of human endometrial stromal via the JNK/Erk1/2-Stat3-VEGF pathway but also promote the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. Conclusion: Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings.The glandular cells and stromal cells from late proliferative endometrium(n=7) and latesecretory endometrium(n=5) were incubated with 10-8mol/ L E2, 10-7mol/ L P4 and 10-8mol/ L E2+1O-7mol / L P4 with an aim of studying the effect of steroid hormones on prostaglandins (PGS)re-leasing from endometrium. It was demostrated that 10-8mol / L E2 and 10-8mol / L E7+1O7mol / LP4 significantly increased PG F2α:output by primary cultures of glandular cells isolated from lateproliferative endometrium. No effects was found on stromal cells from late proliferative endometrium,and stromal and glandular cells from late secretory endometrium. 10-7mol / L P4 didn’t effect thePGF2α output on glandular and stromal cells isolated from late proliferative and late secretoryendometrium PGE2 was not affected by steroid hormones.The results indicate that endometrial glandsare targets for the E2-stimulated increase in PGF2α output by late proliferative endometrium.
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Abstract The uterine endometrium of swine is comprised of luminal epithelial, glandular epithelial, and stromal cells that secrete the luteolysin, prostaglandin F 2α (PGF 2α ), during late diestrus. However, which of these cells contribute the most to luteolytic PGF 2α secretion is unknown because the cellular composition of the endometrium has not been quantified. Therefore, this study quantified the cellular composition of the endometrium on days 12 and 16 postestrus by histologic and morphometric analyses. On day 12, the endometrium consisted predominantly of stromal cells (47% of total cell quantity) and glandular epithelial cells (37%), whereas luminal epithelial cells represented only 16% of the total of the three cell types. The number of glandular epithelial cells tended to increase ( P < 0.10) between days 12 and 16, such that they comprised 45% of the endometrium by day 16, while the number of stromal and luminal cells did not change and accounted for 45% and 10% of the cells, respectively. Luminal epithelial cells had a 58% greater cross‐sectional area ( P < 0.001) than glandular epithelial cells, whereas glandular epithelial cells had a 22% greater area ( P < 0.001) than stromal cells. Glandular epithelial cells decreased ( P < 0.001) in cross‐sectional area between days 12 and 16, whereas the area of luminal epithelial and stromal cells remained unchanged. These results indicate that the porcine endometrium is comprised predominantly of stromal and glandular epithelial cells that are likely to contribute substantially to endometrial PGF 2α secretion during luteolysis. The contribution of glandular epithelium to luteolytic PGF 2α secretion probably increases during diestrus as the number of these cells increases. Anat Rec Part A 270A:59–66, 2003. © 2003 Wiley‐Liss, Inc.
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